Process of manufacture of stilboestrol and related compounds



. Patented July 1, 1941 raocass or mnursc'ruaa or am.- noes-nor. sun arm-ran comrounps Louis I. I'ieaer, Cambridge, Mass., and Walter G.

Clrktlanaen, Glen lik N. 1.; said Christiansen ali nor to 8.1L, Squibb 4; Sons, New N. 1., a corporation of New York No Application May 17, 1940,

, Serial No. 335,820

York.

'1 Claims. .(Cl. 260-613) This invention reiatesto, and has for its object the provision of: 1) a method of preparin compounds of the general formula HO-ClHi-C (lower alkyl) (lower alhvl) C;HOH-notably 4, 4'-dihydroxy-alpha, beta-diethyl-stilbene (stilboestrol)- and (2) amethod of preparing compounds of the general formula wer alkyl) (lower alkyl) stilboestrol is a valuable therapeutic agent, being estrogenically active. It has priorly been prepared by Dodds et al. (Nature 141, 247, 1938), but their method is unsatisfactory in that it gives poor yields.

The method of this invention essentially involves the conversions schematically represented as follows:

(lowerslkyl) e. g., 4-(p-anisyl) -hexanone-3 (a) +Grixnard reagent prepared from halo en-C H 0 l e alkyl),e. 3.. from p-bromo-anisole x (ow r (lower alkyl) (lower alhyl) 00'! alkyl) e. g, 4, 4'-dimethon-alpha, beta-diethyl-alphahydroxy-diphenylethane (b) +Dchydratin s am. P(haloen)| (lower alkyl)CiH|-('l=(|3-CsHc-0 (l0wer slkyl) (l er dbl) (lo er a e. g., 4, 4'-dimethoxy-alpha. beta-diethyl-stilbene (c) +De-alk 11ating agent, a. alcoholic 1:01! 110-- .m-c (lower nun-=0 (lower an n-cim-orr e. 8.. stilboestrol.

Preferably, the de-alkylation step (c) aerfected by reacting with a Grignard-reagent of Y the group consisting of (315M331, CsHsMgBr, and

CiHsMgI. as described and claimed in Braker et al. application Serial No. 275,794, filed May 26, 1939.

The invention will be explained in detail in connection with the manufacture of stilboestrol.

Illustrative examples follow.

trample 1 (a) A solution of 9 g. i-(p-anisyl) -hexanone-3 in ether isadded'dropwise with stirring to an ether solution of the Grignard reagent prepared from 9 g. p-bromo-anisole' and 1.15 3. magnesium metal. The mixture is refluxed for two hours and treated with an iced solution of ammonium chloride: the ether layer is separated, the ether removed therefrom by distillation, and the residue subjected to steam distillation to remove byproducts of thereaction. The portion nonvolatile with steam (about 5 g.) is recrystallized from 95% ethanol toyield about 2 g. of 4, 4'-dimethcity-alpha, beta-diethyl-alpha-hydroxy-diphenylethane, melting at-114-1'7" C. (uncorn) (b) 2 g. 4, 4'--dimethoxy-alpha, beta-diethyl alpha-hydroxy-diphenyl-ethane and 2 cc. phosphorus tri-bromide are mixed and heated on a steam bath for four hours. The reaction mixture is poured into 12 cc. water with stirring, and the crude product so obtained is filtered, washed with water, and crystallized from alcohol. 4, 4-dimethoxy-alpha, beta-diethyl-stilbene is thus obtained as a white crystalline material melting at 122-123 c.

(c) 4, 4'-dimethoxy-alpha, beta-diethyl-stil- .bene is demethylated by treating it with alcoholic KOH and heating in a sealed tube to 205 C.;

on crystallizing from aqueous alcohol, stilboestrol is obtained as colorless plates melting at 167- 168 C.

Example 2 Conversions (a) and (b) are effected as detailed in Example 1. s '(c) 11.6 3. magnesium is suspended in cc. ether, and a solution 01' '72 g. methyl iodide in 250 cc. ether is added with stirring. 60 g. 4, 4'- dimethoxy-alpha, beta-diethyl stilbene is then added, and the ether is distilled from the mixture.- The residue is heated and its temperature so.

controlled that the reaction temperature never rises above 0., the operation requiring frequent removal of the source of heat; the reaction period is about an hour, during which ethane is evolved, and completion of the reaction is indicated by the cessation of evolution of ethane.

The residue is decomposed with ice water and hydrochloric acid, and the material so obtained is filtered, washed with water, and dissolved in dilute sodium hydroxide solution: the alkaline solution is filtered, the filtrate acidified withhy- ,drochloric acid, andthe precipitated product fil-- tered, washed with water, and vacuum-dried. When recrystallized from acetic acid, stilboestrol is obtained as a white crystalline material of melting point 166468 (l. (uncorr):

Manifestly, homologs of the 4-(p-anisyl)- hexanone-iiand/or of the p-anisyl-magnesium bromide (wherein the methyl of the methoxy groups is replaced by other lower-alkyl groups,

- such as ethyl. propyl, or butyl) may be used in the foregoing examples to produce stilboestrol. Also, homologs of stilboestrol, i. e. compounds anisole, reacting the resulting carbinol with a dehydrating agent, and reacting the dehydration product with a de-meth'ylating agent.

4. The method of preparing a compound of the general formula HO,CoH-l C (lower alkyl) :0

(lower allrylii-CaHa-OH, .which' comprisesreembodyinglower-alkyl groups other than ethyl (inter alia, methyl, propyl, and butyl) in the alpha and/or beta positions, may be prepared than para to the linkage between the benzene? 1 nuclei may be prepared by starting with'conl-v acting a compound of the general formula (lower o1l l o-c.HlcH-c=0 (lower alkyl) (lower alkyl) withia Grignard reagent prepared from a compound of the general formula halogen-06H? O-(lower allgyl), reacting the resulting carbinol with a phosphorus trihalide, and reacting the repounds correspondingly-isomeric to i-ip-anisyl) hexanone-3 and/or p-anisyl-magnesium bromide (or their homologs).

The invention may be variously otherwise embodied, within the scope of theappen'ded claims.

We claim: I

1. The method of preparing a compound of the general formula HOCoH4-C(lower alkyl) =C (lower alkyl).CoH 4-OH. vwhich comprises reacting a compound of the general formula (lower alkyl) (lower alhyl) with a Grignard reagent preparedfrom a compound of the general formula haiogen-CaHo- O(lower alkyl) reacting the resulting carbinol with a dehydrating agent, and reacting the dehydration product with a de-alkylating agent. 2. Themethod of preparing a 4,4'-dihydroxyalpha, beta-di-(lower alkyl) -stilbene which comprises reacting a compound of the general formula I (lower olk 1)-o@-( m-c=o owe: alkyl) (lower alkyl) with a Grignard reagent prepared from a comv pound of the general formula balogenOO-(lower alkyl) 'reacting' the resulting carhinol with a dehydrating agent, and reacting'the dehydration suiting dehydration product with a Grignard reagent of-' the group consisting of CHaMgI, CaHsMgBr, and CsHsMgI.

5. The method of preparing a compound of the general formula which comprises reacting a compound of the gen-: eral formula (lower BIkYI)O CQBA-'CHC=O (lower alkyl) (lower alkyl) with a G rignard reagent prepared from a compound of the general formula halogenCeH4 O-(lower alkyl).

6. The method of preparing a compound of the general formula (lower alkyD-O- I (lower alkyl) (lower aikyl) *which comprises reacting a. compound of the general formula (lower alkyll-O an-( i=0 (lower alkyl) (lower alkyl) with a Grignard reagent prepared from a compound of the general formula halogen-O-O-(lowcr alkyl) 0(lower alkyl) U 

